Re-sensitizing ER-Alpha Mutant Breast Cancer Cells to Hormonal Therapy
Re-sensitizing ER-Alpha Mutant Breast Cancer Cells to Hormonal Therapy
批准号:
9302315
负责人:
Rong Li
金额:
$16.58万
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-07-01 至 2018-06-30
关键词:
ABL1 geneAgonistAnabolismArchivesAromatase InhibitorsBinding SitesBreast Cancer CellBreast Cancer TreatmentChromatinClinicalClinical TrialsDataDevelopmentDrug resistanceEstrogen AntagonistsEstrogen Receptor 2Estrogen Receptor betaEstrogen ReceptorsEstrogen receptor positiveEstrogensExhibitsFamilyGenetic TranscriptionGrowthHeterodimerizationHormonesHot SpotHumanIn VitroLaboratoriesMammary NeoplasmsMediatingModalityMolecularNeoplasm MetastasisOutcomePatientsPharmacologyPhosphoric Monoester HydrolasesPhosphorylationPhosphotyrosinePositioning AttributeProtein Tyrosine KinasePublishingResistanceSamplingSignal TransductionTestingTherapeuticTranscriptional ActivationWorkXenograft ModelXenograft procedurebasec-abl Proto-Oncogenesclinically relevantdeep sequencingestablished cell lineexperimental studygenome-widehormone therapyimprovedinhibitor/antagonistinnovationinsightkinase inhibitormalignant breast neoplasmmammary gland developmentmembermouse modelmutantnoveloutcome forecasttherapy resistanttooltumor growthupstream kinase
中文摘要
摘要
大多数乳腺癌患者雌激素受体(ERα)呈阳性。在激素治疗的同时
改善约一半ERα阳性乳腺癌患者的临床结果,无论是初治还是后天
耐药性是一个重大的临床挑战。在几个潜在的机制中,热点
已知ERα的突变由于其雌激素非依赖性转录而产生治疗耐药
活动。因此,减轻这些ERα突变体的异常转录活性有望克服
ER-α阳性乳腺癌治疗的耐药性。作为急诊室大家庭的第二位成员,
内质网β能够通过异源二聚和/或竞争共同的方式干扰ERα的活性
染色质结合部位。ERα的这种ERβ干扰功能可以被用来克服
治疗耐药的ERα突变体。然而,这种方法的临床可行性还远远没有得到充分的探索,因为
关于ERα干扰ERβ活性是如何被动员的,目前还知之甚少。
我们的初步工作在ERβ中发现了一个重要的磷酸酪氨酸开关。具体来说,
我们发现,未磷酸化的ERβ在异二聚化和功能干扰方面特别有效
和ERα一起。因此,我们假设非磷酸化ERβ在ERα阳性乳腺癌中可能有帮助
克服ERα突变介导的治疗耐药。我们进一步设想,药理制剂
微调ERβ的磷酸化酪氨酸状态可能有助于临床刺激其ERα干扰
活动。我们将通过两个具体的目标来检验这一新的假设。首先,我们将使用体外和患者-
确定ERβ磷酸化状态对ERα介导的治疗的影响的衍生异种移植模型
抵抗。第二,我们将使用分子和药理学工具来阐明
ERβ的磷酸化状态调节ERα/β的串扰。
通过聚集特定形式的ERβ来克服治疗耐药性的概念代表了一种
新奇的概念。此外,由于磷酸酪氨酸开关上游激酶的抑制剂是
临床上可用的ERβ特异性激动剂在人类中耐受性良好,我们的工作提供了
微调ERβ活性的可用药靶点和治疗ERα阳性乳腺的迫在眉睫的可译性
癌症。我们提出的研究承诺在理解如何
克服激素治疗的治疗阻力,这是乳腺癌治疗中的一个紧迫的临床挑战。
英文摘要
ABSTRACT
The majority of breast cancer cases are estrogen receptor (ERα)-positive. While hormonal therapy
improves clinical outcomes for about half of patients with ERα-positive breast cancer, de novo or acquired
resistance represents a significant clinical challenge. Among several underlying mechanisms, hot-spot point
mutants of ERα are known to confer therapeutic resistance due to their estrogen-independent transcriptional
activity. Thus, mitigating aberrant transcription activity of these ERα mutants holds promise for overcoming
therapeutic resistance in treatment of ERα-positive breast cancer. As the second member of the ER family,
ERβ is capable of interfering with ERα activity through heterodimerization and/or competing for common
chromatin binding sites. This ERα-interfering function of ERβ could be utilized to overcome the activity of
therapeutically resistant ERα mutants. However, clinical feasibility of this approach is vastly under-explored, as
little is known about how ERα-interfering activity of ERβ is mobilized.
Our preliminary work discovered a functionally important phosphotyrosine switch in ERβ. Specifically,
we found that unphosphorylated ERβ is particularly potent in heterodimerization and functional interference
with ERα. We therefore hypothesize that unphosphorylated ERβ in ERα-positive breast cancer can help
overcome ERα mutant-mediated therapeutic resistance. We further envision that pharmacological agents
that fine-tune the phosphotyrosine status of ERβ could be clinically useful in stimulating its ERα-interfering
activity. We will test this novel hypothesis through two Specific Aims. First, we will use in vitro and patient-
derived xenograft models to determine the impact of ERβ phosphorylation status on ERα-mediated therapeutic
resistance. Second, we will use molecular and pharmacological tools to elucidate the mechanism by which
ERβ phosphorylation status regulates the ERα/β crosstalk.
The concept of overcoming therapeutic resistance by rallying a particular form of ERβ represents a
novel concept. Furthermore, because the inhibitor of the upstream kinase for the phosphotyrosine switch is
clinically available and ERβ-specific agonists are well tolerated in humans, our work provides multiple
druggable targets for fine-tuning ERβ activities and imminent translatability for treating ERα-positive breast
cancer. Our proposed study promises both conceptual and translational advances in understanding of how to
overcome therapeutic resistance to hormonal therapy, a pressing clinical challenge in breast cancer treatment.
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